nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.17650/2311-1267-2018-5-3-43-55nodgo-405Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESМодельные регуляторные сети для белков, активируемых и ингибируемых в процессе индуцированной гранулоцитарной дифференцировкиModel regulatory networks for proteins that are activated and inhibited in the process of induced granulocyte differentiationНовиковаС. Е.NovikovaS. E.

Светлана Евгеньевна Новикова.

119121, Москва, ул. Погодинская, 10, стр. 8

10, Bldg. 8 Pogodinskaya St., Moscow, 119121

novikova.s.e3101@gmail.comТихоноваО. В.TikhonovaO. V.

119121, Москва, ул. Погодинская, 10, стр. 8

10, Bldg. 8 Pogodinskaya St., Moscow, 119121

КурбатовЛ. К.KurbatovL. K.

119121, Москва, ул. Погодинская, 10, стр. 8

10, Bldg. 8 Pogodinskaya St., Moscow, 119121

ВахрушевИ. В.VakhrushevI. V.

119121, Москва, ул. Погодинская, 10, стр. 8

10, Bldg. 8 Pogodinskaya St., Moscow, 119121

ЗгодаВ. Г.ZgodaV. G.

119121, Москва, ул. Погодинская, 10, стр. 8

10, Bldg. 8 Pogodinskaya St., Moscow, 119121

ФГБНУ Научно-исследовательский институт биомедицинской химии им. В.Н. ОреховичаРоссияV.N. Orekhovich Research Institute of Biomedical ChemistryRussian Federation201814092018534355Copyright © Новикова С.Е., Тихонова О.В., Курбатов Л.К., Вахрушев И.В., Згода В.Г., 20182018Новикова С.Е., Тихонова О.В., Курбатов Л.К., Вахрушев И.В., Згода В.Г.Novikova S.E., Tikhonova O.V., Kurbatov L.K., Vakhrushev I.V., Zgoda V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/405

Дифференцирующая терапия с использованием полностью транс-ретиноевой кислоты (ATRA) с успехом применяется для лечения острого промиелоцитарного лейкоза (ОПЛ). В то же время развитие резистентности и синдрома дифференцировки в качестве побочного эффекта является основанием для более глубокого исследования молекулярной основы дифференцирующей терапии и поиска альтернативных подходов к лечению. Используя обработанные ATRA-клетки линии HL-60 в качестве модельного объекта, мы определили 76 активируемых и 101 ингибируемый белок с помощью масс-спектрометрического профилирования без использования стабильных изотопных меток. Применив биоинформатический подход, мы получили модельные схемы регуляции ингибируемых и активируемых белков, ключевыми молекулами которых оказались деацетилаза гистонов 1 (HDAC1) и транскрипционный корепрессор RNF96 соответственно. Обе предсказанные ключевые молекулы были зарегистрированы в клетках линии HL-60 на уровне белка наряду с молекулами Cdk2, DNA-PKcs, Ubc9 и HMGIY в модельной схеме, регулирующей активируемый кластер белков, и протеинкиназой p38 альфа, вовлеченной в схему регуляции ингибируемых белков. Целевое фармакологическое воздействие на эти молекулы может иметь антипролиферативный эффект и представлять альтернативный терапевтический подход для борьбы с ОПЛ.

Differentiation therapy with all trans retinoic acid (ATRA) is successfully used for the treatment of acute promyelocytic leukemia (APL).  At the same time, the development of the resistance and the differentiation syndrome as a side effect is a reason to explore and examine in greater depth the molecular basis of the differentiation therapy and to search the alternative paradigm of the treatment. By the use of ATRA-treated HL-60 cell line as a model object, we have estimated 76 activated and 101 inhibited proteins by the label-free mass-spectrometric profiling. By applying the bioinformatic approach we have obtained model schemes of regulation of the inhibited and  activated  proteins  whose  key  molecules  turn  out  to  be  the  histone  deacetylase  1  (HDAC1)  and  the  transcriptional  corepressor (RNF96) respectively. Both of predicted key molecules have been detected in HL-60 cell line at the proteome level in conjunction with Cdk2, DNA-PKcs, Ubc9 and HMGIY molecules in the model scheme regulating the activated protein cluster and the protein kinase p38 alpha involved in the regulating scheme of the inhibited proteins. The pharmacological targeting of these molecules may have an antiproliferative effect and provide the alternative approach to APL treatment.

ATRAклетки линии HL-60гранулоцитарная дифференцировкамасс-спектрометрияпоиск ключевых регуляторовтранскрипционные факторыATRAHL-60 cellsgranulocyte differentiationmass spectrometrykey regulators searchtranscription factorsПрограмма фундаментальных научных исследований государственных академий наук на 2013–2020 гг. с использованием оборудования Центра коллективного пользования «Протеом человека» (ФГБНУ «Научно-исследовательский институт биомедицинской химии им. В.Н. Ореховича»), поддержанного Минобрнауки России (уникальный идентификатор проекта RFMEFI62117X0017)Program of Fundamental Scientific Research of the State Academies of Sciences for 2013–2020 using the equipment of the Center for Collective Use “Human Proteome” (V.N. Orekhovich Scientific Research Institute of Biomedical Chemistry), supported by the Ministry of Education and Science of Russia (unique identifier of the project RFMEFI62117X0017)ReferencesDi Girolamo F., Lante I., Muraca M., Putignani L. 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The authors declare that there are no conflicts of interest present.